Lactose Intolerance
Dairy foods are an important source of protein, riboflavin and calcium for the United States, Europe, Asia, Africa and the many other areas of the world. However, many individuals suffer from lactose intolerance. This condition results from absence or insufficient production of the enzyme lactase. Acquired lactase deficiency is the most common disorder of complex carbohydrate absorption throughout the world, affecting up to 75% percent of the world's population. In the United States, 15% of Caucasians, over 50% of Hispanics and over 80% of African Americans suffer from lactose intolerance. The disorder is characterized by gastrointestinal symptoms of excessive gas production, abdominal pain, cramps, bloating and diarrhea after excessive consumption of lactose-containing foods such as dairy and dairy-based products.
In infancy, mammals have a high level of lactase activity in the lining of the upper intestinal tract, because they depend on lactose as the primary carbohydrate in their diet. However, in humans, the lactase expression is diminished by about 90% between ages two and five. This condition is called primary lactase deficiency. Many Northern Europeans, some Western Europeans, Mediterraneans and their descendants carry a mutation that prevents this natural decrease in lactase production. These individuals are able to consume milk as adults. However, large portions of the world population, such as Southern Europeans, East Asians and Sub-Saharan Africans have primary lactase deficiency.
Secondary lactase deficiency results from injury or disease of the small intestine. For example, celiac disease, inflammatory bowel syndrome (IBS) and Crohn's disease are often accompanied by lactase deficiency. These diseases occur in all ethnic groups.
Lactose Metabolism
Lactose is a disaccharide of glucose and galactose linked by a beta-D-glycosidic bond. The disaccharide is digested into its individual sugars by the lactase (beta-D-galactosidase) produced in the small intestine by the cells of the intestinal brush border. Glucose and galactose are absorbed in the small intestine. When lactase is absent from the small intestine, undigested lactose reaches the large intestine. There the resident bacteria metabolize lactose through fermentation generating gas. The gas is responsible for symptoms such as pain, pressure, cramps and flatulence. In addition, the undigested lactose increases osmotic pressure in the intestine, causing increased excretion of water and diarrhea.
Supplementing Lactase
There are several ways of delivering lactase to the gastrointestinal tract. As a simplest method, one can ingest a tablet of the isolated enzyme. Enzymes that break down lactose may be isolated from a variety of microorganisms, such as yeast, bacteria and fungi, such as Saccharomyces fragilis, Torula cermoris, Lactobacillus bulgaricus, Aspergillus oryzae, Aspergillus flavus and Asperillus niger. For example, U.S. Pat. No. 2,762,749 teaches preparing a lactase enzyme from budding yeast (Saccharomyces and Torula genuses) to supplement milk products where lactose crystallization is a problem. Lactase from fungi, such as Aspergillus, is described in U.S. Pat. No. 3,620,924. Isolating bacterial lactase (from the genus Bacillus) is described in U.S. Pat. Nos. 4,179,335, 4,237,230 and 4,323,651.
Several problems are associated with lactase replacement products. First, these products are not retained in the gastrointestinal tract. Lactase pills must be taken with each diary-containing meal. When the subject forgets to take the pill, or is unaware that food contains dairy, the symptoms of lactose intolerance are bound to recur.
Another problem is that many lactase enzymes from other species function poorly in the mammalian small intestine. The pH of the duodenum, where most of the normal lactose digestion occurs, is between 6.0 and 6.5. In contrast, as taught in the U.S. Pat. No. 6,562,339, a fungal lactase has a pH optimum of 4.8 and is only 10% active at pH 6.5. Many bacterial beta-galactosidases have a pH optimum above 7.0. Fortunately, a few enzymes from the Bacillus genus, as described for example, in U.S. Pat. No. 4,179,335, have a pH optimum near 6.0.
Another way to supplement lactase involves ingesting live or killed lactase-producing bacteria. For example, it is known that persons with mild lactose intolerance are able to tolerate yogurt but not milk, although both products contain the same amount of lactose. This is due to the fact that bacteria present in yogurt, such as Streptococcus thermophilus, Lactobacilli, Acidophilus and Bifidus species, express functional lactase. Thus, to improve the ability to digest lactose, one may consume yogurt products containing live and active cultures of these bacteria. Alternatively, one can ingest capsules that contain lyophilized live yogurt bacteria, as taught for example, in the U.S. Pat. No. 6,008,027. For an enhanced effect, bacteria can be combined with isolated lactase in the same enterically coated capsule, as taught in the U.S. Pat. No. 5,952,021 or Application Publication No. 2005/0100535.
Besides yogurt bacteria, other lactase-producing species can be used to improve lactose tolerance. For example, Korean researchers have isolated strains with lactase activity and good resistance to gastric acid. These strains come from Lactobacillus fermentum, (WIPO Publication KR3064030A), Lactococcus lactis (WIPO Publication KR4044300A) and Lactobacillus plantarum (WIPO Publication KR2088797A).
Unfortunately, physicians report limited success with treating lactose intolerance with naturally occurring bacterial cultures. The review of the literature conducted by family practitioners at the University of Pittsburg (“Do probiotics reduce adult lactose intolerance?” J Fam. Pract., 2005; v. 54, No. 7, p. 613-620) concluded that overall, the strategy was ineffective. The authors suggest that this is due to variation in bacterial viability and ability to produce lactase between the different dairy products and supplements. According to the study, with a few exceptions, most of these products do not provide sufficient lactase activity to alleviate the symptoms of lactose intolerance.
The symptoms of lactose intolerance were not relieved even when the most promising bacterium, Lactobacillus acidophilus was used. Among the yogurt bacteria, L. acidophilus has one of the highest natural levels of lactase and superior ability to adhere to the intestinal wall. Nevertheless, a Tufts University study “A randomized trial of Lactobacillus acidophilus BG2F04 to treat lactose intolerance”, Am. J. Clin. Nutr. 1999, 69:140-146, concluded that even this bacterium was ineffective against the symptoms of lactose intolerance.
Using genetically-engineered bacteria to digest lactose is also known in the art. For example, U.S. Pat. No. 6,833,260 describes bacteria engineered to produce bacterial beta-galactosidase under the control of a constitutive promoter. Compared to the parent strain, the engineered bacteria produce more enzyme, although it is still of bacterial origin.
A more aggressive method of treating lactose intolerance involves gene therapy where the lactase gene is delivered directly into the cells of the intestinal wall, as described in U.S. Pat. No. 6,110,456. This method has several disadvantages. First, virus-driven gene therapy carries its own risks associated with the vector and the helper virus. Second, the target cells for the therapy, the intestinal epithelium, are constantly shedding. Unless the stem cells at the base of the inner layer of the intestinal wall are transformed with the new gene, the expression of lactase will be temporary. The newly emerging layers of intestinal cells would need to be repeatedly retransformed with another dose of the gene.
In summary, there is a need for a safe but long-lasting treatment of lactose intolerance. Ideally, one treatment would last for months without re-application. An ideal treatment would involve a lactase enzyme optimized for action under the conditions found in the mammalian small intestine.